摘要
帕博西尼(palbociclib)是一种治疗转移性乳腺癌的新药,于2015年获得美国食品药品监督管理局批准上市。本文较全面地报道了帕博西尼的9种合成工艺路线,并进行了相应的评价。通过对这些合成工艺的比较和分析,发现帕博西尼的合成主要包括4个关键步骤:构建吡啶酮并嘧啶环、2位引入[5-(1-哌嗪基)-2-吡啶基]氨基、6位引入乙酰基和8位引入环己基。传统的合成路线存在诸多缺点,如反应步骤多、采用价格昂贵的金属钯以及有毒的有机锡化物和强碱二(三甲基硅基)胺基锂(Li HMDS)、部分操作条件苛刻和总收率低。新开发的路线或通过选择恰当的原料和反应,或选用新型反应器如微波-超声波联合反应器,或通过"一锅煮"方式来减少反应步骤,避免采用钯类和有机锡类化合物,从而构建反应步骤少、收率高、环境友好和较具有工业化价值的合成路线。帕博西尼的合成路线总体上向着原辅材料价廉易得、所采用试剂环保、反应路线短、操作简单、反应条件温和及总收率高的方向不断改进。就现有的合成路线而言,倘若能寻找到操作简单的催化剂代替强碱Li HMDS,以2,4-二氯嘧啶为起始原料的合成路线8具有较强的工业化前景;倘若能解决微波-超声波联合反应器的放大问题,以2-乙酰基-2-丁烯酸甲酯为起始原料的合成路线6是最具工业化前景的路线。此外,本文也介绍了具有更好的药代性质和体内稳定性的氘代帕博西尼的合成工艺,可根据帕博西尼的先进合成路线对此工艺进行改进。
Palbociclib,a new drug for treating metastatic breast cancer,was approved by the FDA in 2015.Nine synthesis routes of palbociclib were reviewed in this paper.The comparison and analysis of these synthesis routes showed that the synthesis of palbociclib had four key steps：constructing pyrimidinopyridone,introduction of 5-piperazin-1-yl-pyridin-2-ylamino in 2-position,acetyl in 6-position,and cyclohexyl in 8-position.Traditional synthesis routes have many disadvantages,such as too many reaction steps,used expensive metal palladium,toxic organotin compounds and Li HMDS,severe reaction conditions required,and low gross yields.The newly-developed synthesis routes improved the synthesis process of palbociclib through selecting proper raw materials and reactions.Newly developed reactors（like microwave-ultrasonic reactors） or one-pot routes reduced the reaction steps and avoided using palladium and organotin compounds so that the synthesis routes resulted in few reaction steps,high yields,environment-friendliness,and asset of industrialization.The synthesis routes of palbociclib are continuously improved by using cheap and readily available rawmaterials and environmentally benign agents,reducing synthesis steps,simplifying operation,having gentle reaction conditions and high total yields.Among the reported synthesis routes,the route 8 showed the potential of commercialization if Li HMDS can be replaced by a catalyst with simple operation.The route 6 has the greatest potential for industrialization if the scale-up of microwave-ultrasonic reactors can be solved.Besides,the synthesis method of deuterated palbociclib,which has better pharmacokinetics property and higher stability in vivo,is also introduced,and can be further improved according to the advanced synthesis routes of palbociclib.
出处
《化工进展》
EI
CAS
CSCD
北大核心
2018年第1期242-251,共10页
Chemical Industry and Engineering Progress
基金
福建省中青年教师教育科研项目(JAS151245)
关键词
抗乳腺癌
帕博西尼
合成
anti-breast cancer drug
palbociclib
synthesis
